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Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts

A technology of o-chloromandelic acid and diastereomers, applied in the field of medicinal chemistry, can solve the problems of small scale, few resolutions, and expensive resolution agents, and achieve the effects of easy separation, low cost, and simple synthesis methods

Inactive Publication Date: 2012-07-25
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the high price of the above-mentioned resolving agents or the control of drugs, these methods have not been widely used, but this method is one of the few methods that can achieve industrial production
[0019]4. Some other methods: electrochemical method, extraction and resolution method, chromatographic resolution method, and electrophoresis resolution method have a common feature that the resolution scale is very small, only As a detection method in the laboratory, it is very difficult to realize industrial production

Method used

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  • Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts
  • Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts
  • Resolution method for 2-chloromandelic acid by crystalizing diastereomeric salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 R in the general formula II 1 =o-CH 3 , R 2 =-CH 3， R 3 =-CH 3 The (S / R)-2 (S / R)-N,N-dimethyl-1-o-tolyloxy-3-amino-2-propanol is the chiral resolving agent, and R in the general formula III 4 =o-OCH 3 , R 5 =-CH 3， R 6 =-CH 3 Resolution of (S / R)-3 (S / R)-N,N-dimethyl-1-o-methoxyphenoxy-3-amino-2-propanol as a nucleation inhibitor for racemization o-chloromandelic acid 1.

[0049] 1. Step (1)

[0050] 18.6g (0.1mol) racemic o-chloromandelic acid, 18.8g (0.09mol) (S) -2 , 2.25g (0.01mol) (S)-3 in 150ml of ethanol, magnetically stirred at 30°C for 5-6 hours, then left to stand, until solid precipitated, suction filtered after 6 hours to obtain a white solid R -1 -S -2 20.9g (0.053mol, yield 82% (calculated based on the amount of single-configuration o-chloromandelic acid)).

[0051] 2. Step (2)

[0052] The solid R obtained by suction filtration in the first step -1 -S -2 Dissolve 20.9g in 100ml of water, add 26.5ml of dilute sulfuric acid a...

Embodiment 2

[0053] Embodiment 2: R in general formula II 1 =-H, R 2 =-C 2 h 5， R 3 =-C 2 h 5 The (S / R)-2 (S / R)-N,N-diethyl-1-phenoxy-3-amino-2-propanol is the chiral resolving agent, and R in the general formula III 4 =o-NO 2 , R 5 =-CH 3， R 6 =-C 2 h 5 Resolution of (S / R)-3 i.e. (S / R)--N-methyl-N-ethyl-1-o-nitrophenoxy-3-amino-2-propanol as a nucleating inhibitor Racemic o-chloromandelic acid 1.

[0054] 1. Step (1)

[0055] Add 18.6g (0.1mol) of racemic o-chloromandelic acid, 11.2g (0.05mol) of (S)-2, 12.7g (0.05mol) of (S)-3, and 150ml of ethyl acetate into a 250ml round bottom flask , stirred magnetically at 30°C for 5-6 hours, then stood still, and after 6 hours, suction filtered to obtain a white solid R -1 -S -2 15.5g (0.038mol, yield 76% (calculated based on the amount of single-configuration o-chloromandelic acid)).

[0056] 2. Step (2)

[0057] The solid R obtained by suction filtration in the first step -1 -S -2 Dissolve 15.5g in 50ml of water, add 19ml o...

Embodiment 3

[0059] Embodiment 3: R in general formula II 1 = o-Cl, R 2 =-C 2 h 5 , R 3 =-CH 3 The (S / R)-2 (S / R)-N-methyl-N-ethyl-1-o-chlorophenoxy-3-amino-2-propanol is a chiral resolving agent, the general formula R in III 4 =o-NH 2 , R 5 =-C 2 h 5， R 6 =-C 2 h 5 Resolution of (S / R)-3 (S / R)-N,N-diethyl-1-o-aminophenoxy-3-amino-2-propanol as a nucleation inhibitor for racemic o Chloromandelic acid 1.

[0060] 1. step one)

[0061] Add 18.6g (0.1mol) of racemic o-methylmandelic acid, 17.07g (0.07mol) of (S)-2, 7.1g (0.03mol) of (S)-3, and 150ml of isopropanol into a 250ml round bottom flask , stirred magnetically at 90°C for 3-4 hours, then stood still, and after 6 hours, suction filtered to obtain a white solid R-1-S-2 17.2g (0.04mol, yield 80% (in a single configuration Calculation of the amount of o-chloromandelic acid)).

[0062] 2. Step (2)

[0063] The solid R obtained by suction filtration in the first step -1 -S -2 Dissolve 17.2g in 50ml of water, add 38ml o...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a diastereomeric resolution method of 2-chloromandelic acid. According to the method, 2-chloromandelic acid with a single configuration is prepared by use of a chiral amino alcohol as a resolving agent. The ee (enantiomeric excess) of prepared 2-chloromandelic acid with the single configuration is more than 99%, the yield is not less than 75%, the synthetic method is simple, and the cost is low, so that the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a resolution method for preparing single-configuration o-chloromandelic acid by using a chiral resolution agent and a nucleation inhibitor. Background technique [0002] O-chloromandelic acid is an important intermediate in the synthesis of medicines and dyes, and is widely used in biological and chemical synthesis. Optically active o-chloromandelic acid is an important intermediate in the synthesis of many chiral drugs. R-o-chloromandelic acid is used to prepare the drug clopidogrel of anti-platelet aggregation, and the chemical name of clopidogrel is (+)-( S )- α -(2-Chlorophenyl)-6,7-dihydrothieno[3,2- c ] Pyridine-5(4H)-methyl acetate, which is clinically used to prevent atherosclerosis in patients with myocardial infarction, stroke or patients with a history of peripheral arterial disease, and other widely used platelet inhibitors (aspirin, thiophene Compared wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/56C07C51/42C07B57/00
Inventor 刘宏民王培张恩赵鹏任清华关圆圆
Owner ZHENGZHOU UNIV
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